Fibroblast growth factors (FGFs) are known to play an important role in embryogenesis, tissue homeostasis, and metabolism via FGF receptor (FGFR) signals (Non Patent Literature 1). In humans, 22 FGFs (FGF1 to FGF14 and FGF16 to FGF23) and 4 FGF receptors (FGFR1 to FGFR4; hereinafter, collectively referred to as “FGFRs”) having a tyrosine kinase domain are found. These FGFRs are each constituted by an extracellular region comprising a ligand binding site composed of 2 or 3 immunoglobulin-like domains (IgD1 to IgD3), a single-pass transmembrane region, and an intracellular region comprising the tyrosine kinase domain. FGFR1, FGFR2, and FGFR3 each have two splicing variants called IIIb and IIIc. These isoforms differ in the sequence of approximately 50 amino acids in the latter half of IgD3 and exhibit distinctive tissue distribution and ligand specificity. It is generally known that the IIIb isoform is expressed in epithelial cells, while the IIIc isoform is expressed in mesenchymal cells. Upon binding of FGFs to FGFRs, these FGFRs are dimerized and phosphorylated at their particular tyrosine residues. This phenomenon promotes the recruiting of important adaptor proteins such as FGFR substrate 2α (FRS2α) and induces the activation of many signaling pathways including MAPK and PI3K/Akt pathways. As a result, FGFs and their corresponding receptors control a wide range of cell functions including growth, differentiation, migration, and survival.
The abnormal activation of FGFRs is known to participate in particular types of malignant tumor development in humans (Non Patent Literature 1 and 2). Particularly, findings such as the overexpression of FGFR2 and its ligand, receptor mutations or gene amplification, and isoform switching, have been made as to the association of FGFR2 signal abnormality with cancer. Specifically, a single nucleotide polymorphism (SNP) in intron 2 of the FGFR2 gene reportedly correlates with the risk of breast cancer progression caused by the high expression of FGFR2 (Non Patent Literature 3 and 4). Missense mutations that constitutively activate FGFR2 have been reported in endometrial cancer, ovary cancer, breast cancer, lung cancer, and stomach cancer (Non Patent Literature 2, 3, and 5). Also, the amplification or overexpression of the FGFR2 gene has been reported in stomach cancer and breast cancer (Non Patent Literature 2, 3, and 5). In addition, class switch from FGFR2 IIIb to FGFR2 IIIc is also known to occur during the progression of prostate cancer or kidney cancer and correlate with poor prognosis (Non Patent Literature 6 and 7).
As mentioned above, the association of FGFR2 overexpression or mutations or switching from IIIb to IIIc, with many cancer types suggests the possibility of FGFR2 as an excellent therapeutic target for cancer. In fact, monoclonal antibodies against FGFR2 have been obtained and are under evaluation for their antitumor effects in preclinical trials in order to reveal the role of FGFR2 in oncogenesis and determine the possibility of FGFR2 as a therapeutic target for cancer (Non Patent Literature 8 and 9). All of these antibodies have been shown to have a neutralizing effect that inhibits signaling derived from a ligand for FGFR2 IIIb. Unfortunately, there has been no report on a functional antibody having effector effects such as ADCC or a neutralizing effect on IIIc.